The molecular basis of asbestos induced lung injury.

Asbestos causes progressive pulmonary fibrosis (asbestosis), pleural disease (eVusion and pleural plaques), and malignancies such as bronchogenic carcinoma and malignant mesothelioma. Asbestos is a generic term for a group of naturally occurring hydrated silicate fibres whose tensile strength and resilient structural and chemical properties are ideally suited for various construction and insulating purposes. The toxic eVects of asbestos depend upon the cumulative dose and the time since the first exposure. Asbestos related diseases typically occur after a 15–40 year latency period following initial fibre exposure. The two classes of asbestos fibres, serpentine and amphibole fibres, can each cause pulmonary disease. Serpentine fibres, of which chrysotile is the principal commercial variety, are curlystranded structures whereas amphiboles (crocidolite, amosite, tremolite and others) are straight, rod-like fibres. Chrysotile accounts for over 95% of world asbestos consumption. Asbestos induced pulmonary diseases remain a significant health concern. In the United States over 30 million tons of asbestos have been mined, processed and applied since the early 1900s. Moreover, non-occupational asbestos exposure may originate from existing buildings that contain enormous amounts of the fibres. Finally, it is estimated that the cumulative total number of asbestos associated deaths in the United States may exceed 200 000 by the year 2030. Extensive investigations over the last two decades have revealed some of the pathogenic mechanisms of asbestos pulmonary diseases. A further benefit of these studies is that asbestos induced pulmonary toxicity is an excellent paradigm to explore the mechanisms underlying other common causes of pulmonary fibrosis and malignancy. Asbestos is an established genotoxic agent that can induce DNA damage, gene transcription, and protein expression important in modulating cell proliferation, cell death, and inflammation. 2 7–9 Recent comprehensive reviews have described in detail the histopathological and clinical features of asbestos related diseases 9 10 as well as the evidence implicating various pathogenic pathways of asbestos induced lung diseases including (a) the chemical and structural properties of the fibres, 2 7–9 (b) the lung fibre burden, (c) fibre uptake by pulmonary epithelial cells, (d) iron catalysed free radicals, 12 (e) DNA damage, 14 (f) cytokines/growth factors, 9 15 and (g) cigarette smoke. 9 Notably, no single mechanism fully accounts for all the complex biological abnormalities caused by asbestos. Moreover, the precise pathogenic pathways involved and their regulation are not fully established. In this review we focus on the important new information that has emerged over the last several years concerning the molecular mechanisms of asbestos related diseases. The primary goal of this review is to re-examine the evidence addressing the hypothesis that free radicals, especially iron-catalysed reactive oxygen species (ROS), have an important role in inducing pulmonary toxicity from asbestos exposure.